Breast and ovarian cancers are common, often lethal malignancies in women. Improved survival may result from early detection in-hose at highest risk for cancer. Epidemiologic evidence indicates that women of Jewish ancestry are at high risk of breast cancer (BC). Possible explanations for this high risk include common environmental exposures among Jewish women, or to a high prevalence of inherited mutations increasing susceptibility to breast cancer, or to the interaction of inherited and environmental risk factors. Inheritance plays a role in the development of all human cancers to varying degrees. It is estimated that 5-10% of BC and ovarian cancer (OC) cases occur as part of heritable syndromes due to mutations in highly penetrant genes. The HBOC syndrome is an inherited susceptibility to both carcinoma of the breast and ovary. The risk for BC and OC among these families is extremely variable. The cloning of the BRCA1 gene on chromosome 17q, and a second high-risk locus on chromosome 13q (BRCA2), has provided the opportunity to examine the role of specific BRCA genotypes. The observation that virtually all breast cancer patients of Ashkenazi Jewish ancestry with inherited mutations in BRCA1 carry the same cancer-associated allele (185delAG) paved the way for focused scientific studies of a single BRCA1 mutation. Thus far, there has been no correlation between BRCA1 genotype and clinical phenotype to explain the differences in cancer penetrance and expressivity. Therefore, it is believed that there are additional determinants; modifier genes. Rare alleles of the HRAS1 gene are thought to be an example of a modifier locus. Mutant alleles of this locus represent a major risk factor for cancers of the breast, colorectum, and urinary bladder and for acute leukemia. Preliminary studies in 90 OC patients demonstrated a frequency of rare HRAS1 alleles paralleling the significant association seen with other cancers. We propose to determine whether rare HRAS1 alleles are associated with an increased risk of BC or OC in Jewish women, or whether they influence the occurrence of BC or OC within high-risk families. A unique opportunity is presented to study a significant number of BC patients of Jewish ancestry through a multi- institutional collaboration. Observations on specific HRAS1 allele associations with BC or OC may contribute to our understanding of the phenotypic heterogeneity seen in familial cancer syndromes, while helping us characterize the proportion of "sporadic" BC and OC for which there may be an underlying genetic predisposition. Correlation with clinical/epidemiological data will allow us to delineate possible interactions with environmental or genetic risk factors.